Aminopyridazine → 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amine

HRID 450159

반응식

HRID 450159 반응식
[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[N:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1

참가 물질

7

반응물 3

HCID 230373AminopyridazineHCID 2724254Sodium bis(trimethylsilyl)amideHCID 220368724-(4-chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine

생성물 1

HCID 498693554-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amine수율 18.2%

시약·촉매·용매 3

HCID 176Acetic Acid용매HCID 962Water용매HCID 8028Tetrahydrofuran용매2회

실험 절차

To a solution of 0.159 g (1.67 mmol) of 3-aminopyridazine in THF (3 mL) at 0° C. was added 0.93 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.317 g (0.84 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexane-EtOAc (8:2) then with CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.065 g (18% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amine: mp 271-273° C.; 1H NMR (DMSO-d6) δ 11.16 (br s, 1H), 8.98 (dd, J=4.7, 1.4 Hz, 1H), 8.67 (d, J=8.0 Hz, 1H), 8.61 (d, JHF=8.4 Hz, 1H), 8.08 (t, JHF=52.8 Hz, 1H), 7.86 (dd, J=7.7, 0.7 Hz, 1H), 7.73 (dd, J=9.1, 4.7 Hz, 1H), 7.53-7.43 (m, 2H), 3.86 (s, 4H), 3.75 (s, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.7; H, 4.2; N, 29.5%.

후처리

  1. stirringthe resulting mixture was stirred for 1 hr at RT
  2. extractionextracted with EtOAc
  3. washThe organic layer was washed sequentially with water and aq. NH3
  4. customdried
  5. concentrationconcentrated
  6. washChromatography on alumina, eluting first with hexane-EtOAc (8:2)
  7. customwith CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a white powder
  8. customRecrystallization from ethanol/CH2Cl2

출처 및 근거

ORD 기록
ord-b181d4c922924e3289bc65c3716f180c
출처 데이터셋
uspto-grants-2013_07
특허 번호
US08486939B2

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